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| United States Patent |
5,580,866
|
|
Housley
, et al.
|
December 3, 1996
|
Therapeutic 1,4-thiazepines
Abstract
Compounds of formula I
##STR1##
in which n=0, 1 or 2;
R.sub.1, R.sub.2, R.sub.6 and R.sub.7 independently represent H or alkyl
(optionally substituted by one or more halo);
R.sub.3 and R.sub.4 independently represent H or alkyl or together
represent a group of formula .dbd.NR.sub.12 where R.sub.12 represents H,
hydroxy, alkyl, phenyl or alkoxy; each alkyl, phenyl and alkoxy being
optionally substituted with one or more halo;
R.sub.5 represents: (a) H, (b) alkyl, (c) a group of formula --COR.sub.13
in which R.sub.13 is H, alkyl or phenyl, when R.sub.3 and R.sub.4
represent H or alkyl (optionally substituted with one or more halo), or
(d) a group of formula --S(O).sub.p R.sub.14 in which p=1 or 2 and
R.sub.14 is alkyl or phenyl, when R.sub.3 and R.sub.4 represent H or alkyl
(optionally substituted with one or more halo); each alkyl and phenyl
optionally substituted with one or more halo;
and R.sub.8 to R.sub.11 independently represent H, halo, cyano, nitro,
alkyl alkoxy, alkanoyl, carboxy, alkanoyloxy, carbamoyl (optionally
substituted with alkyl or sulphamoyl (optionally substituted with alkyl of
1 to 4 carbon atoms); each alkyl, alkoxy, alkanoyl or alkanoyloxy
optionally substituted with one or more halo;
have utility in the treatment of seizures and/or neurological disorders
such as epilepsy and/or as neuroprotective agents to protect against
conditions such as stroke.
| Inventors:
|
Housley; John R. (Nottingham, GB2);
Jeffery; James E. (Nottingham, GB2);
Nichol; Kenneth J. (Nottingham, GB2);
Sargent; Bruce J. (Nottingham, GB2)
|
| Assignee:
|
The Boots Company PLC (Notts, GB)
|
| Appl. No.:
|
424464 |
| Filed:
|
May 3, 1995 |
| PCT Filed:
|
November 6, 1993
|
| PCT NO:
|
PCT/EP93/03123
|
| 371 Date:
|
May 3, 1995
|
| 102(e) Date:
|
May 3, 1995
|
| PCT PUB.NO.:
|
WO94/11360 |
| PCT PUB. Date:
|
May 26, 1994 |
Foreign Application Priority Data
| Nov 09, 1992[GB] | 9223441 |
| Nov 09, 1992[GB] | 9223443 |
| Current U.S. Class: |
514/211.09; 540/552 |
| Intern'l Class: |
A11K 031/55; C07D 281/10 |
| Field of Search: |
540/552
512/211
|
References Cited
U.S. Patent Documents
| 3682962 | Aug., 1972 | Dickinson | 260/327.
|
| 4990707 | Oct., 1989 | Mais et al. | 570/210.
|
| Foreign Patent Documents |
| 0368063 | May., 1990 | EP.
| |
| 0565721 | Oct., 1993 | EP.
| |
| 4916M | Apr., 1967 | FR.
| |
| 92/12148 | Jul., 1992 | WO.
| |
| 92/21668 | Dec., 1992 | WO.
| |
| 93/16055 | Aug., 1993 | WO.
| |
Other References
The international search report.
Boudet et al, C. R. Acad. Sci. Paris Series .C, 282, 249-251 (26 Jan.
1976).
Nair et al, Chem. Abs. 71 (25) 124391p (22 Dec. 1969).
Nair et al, Chem. Abs. 8th Coll. Subj. Index 4452s.
Nair et al, Indian J. Chem. 7 (9) 862-865 (1969).
Szabo et al, Chem. Ber. 119 2904-2913 (1986).
Sternbach et al, J. Org. Chem. 30 (8) 2812-2818 (1965).
Szabo et al, Acta Chimica Hungarica 115 (4) 429-437 (1984).
|
Primary Examiner: Bond; Robert T.
Attorney, Agent or Firm: Nikaido, Marmelstein, Murray & Oram LLP
Claims
We claim:
1. A compound of formula I
##STR7##
wherein n is 0, 1 or 2;
R.sub.1, R.sub.2, R.sub.6 and R.sub.7 are H;
R.sub.3 and R.sub.4 are independently H or methyl; or together are selected
from the group consisting of imino, methylimino, phenylimino, hydroxyimino
and methoxyimino;
R.sub.5 is H or methyl, or when R.sub.3 and R.sub.4 are independently H or
methyl, R.sub.5 is selected from the group consisting of formyl, acetyl,
propionyl, benzoyl, methylsulphinyl, methylsulphonyl and ethylsulphonyl;
R.sub.8 is selected from the group consisting of H, methyl, fluoro and
chloro; and
R.sub.9, R.sub.10 and R.sub.11 are each H,
a stereoisomer thereof or a pharmaceutically acceptable salt thereof;
with the provisos that
i) at least one of R.sub.1 to R.sub.11 is other than H;
ii) when n is 0 and R.sub.1 to R.sub.4 and R.sub.6 to R.sub.11 are each H,
then R.sub.5 is other than benzoyl or acetyl; and
iii) when n is 0, 1 or 2, and R.sub.1 to R.sub.3 and R.sub.5 to R.sub.11
are each H, then R.sub.4 is other than methyl.
2. A compound as claimed in claim 1, wherein the compound is selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine oxide;
4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and
6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine,
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
3. A compound as claimed in claim 1, wherein the compound is selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and
6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine,
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
4. A compound as claimed in claim 1, wherein the compound is selected from:
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
and
6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
5. A compound as claimed in claim 1, wherein the compounds is:
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine,
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound of formula I
##STR8##
wherein n=0, 1 or 2;
R.sub.1 and R.sub.2 independently are H or alkyl of 1 to 4 carbon atoms
which is unsubstituted or substituted by at least one halo atom;
R.sub.3 and R.sub.4 independently are H or alkyl of 1 to 4 carbon atoms; or
together represent a group of formula .dbd.NR.sub.12 where R.sub.12 is
selected from the group consisting of H, hydroxy, alkyl of 1 to 4 carbon
atoms, phenyl and alkoxy of 1 to 4 carbon atoms; wherein each alkyl,
phenyl and alkoxy is unsubstituted or substituted by at least one halo
atom;
R.sub.5 is selected from the group consisting of (a) H, (b) alkyl of 1 to 4
carbon atoms, (c) a group of formula --COR.sub.13 wherein R.sub.13 is
selected from the group consisting of H, alkyl of 1 to 4 carbon atoms and
phenyl, when R.sub.3 and R.sub.4 independently are H or alkyl of 1 to 4
carbon atoms which is unsubstituted or substituted by at least one halo
atom and (d) a group of formula --S(O).sub.p R.sub.14 in which p=1 or 2
and R.sub.14 is alkyl of 1 to 4 carbon atoms or phenyl, when R.sub.3 and
R.sub.4 independently are H or alkyl of 1 to 4 carbon atoms which is
unsubstituted or substituted by one or more halo atom; wherein each alkyl
and phenyl is unsubstituted or substituted by at least one halo atom;
R.sub.6 and R.sub.7 independently are H;
R.sub.8 to R.sub.11 independently are selected from the group consisting of
H, halo, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4
carbon atoms, alkanoyl of 1 to 4 carbon atoms, carboxy, alkanoyloxy of 1
to 4 carbon atoms, carbamoyl which is unsubstituted or substituted with
alkyl of 1 to 4 carbon atoms and sulphamoyl which is unsubstituted or
substituted with alkyl of 1 to 4 carbon atoms; wherein each alkyl, alkoxy,
alkanoyl or alkanoyloxy is unsubstituted or substituted by at least one
halo atom,
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
with the proviso that:
(i) when n=0; at least one of R.sub.1 to R.sub.11 is other than H;
together with a pharmaceutically acceptable diluent or carrier.
7. A pharmaceutical composition as claimed in claim 6, wherein
n=0 or 1;
R.sub.1 and R.sub.2 are independently H or methyl;
R.sub.3 and R.sub.4 are independently H or methyl; or together are selected
from the group consisting of imino, methylimino, phenylimino, hydroxyimino
and methoxyimino;
R.sub.5 is H or methyl, or when R.sub.3 and R.sub.4 are independently H or
methyl, R.sub.5 is selected from the group consisting of formyl, acetyl,
propionyl, benzoyl, methylsulphinyl, methylsulphonyl and ethylsulphonyl;
R.sub.6 and R.sub.7 independently are H; and
one of R.sub.8 to R.sub.11 is (a) H, (b) fluoro, (c) chloro, (d) bromo, (e)
iodo, (f) methyl which is unsubstituted or substituted with one or more
halo, (g) methoxy which is unsubstituted or substituted by one or more
halo, (h) nitro, (i) cyano, (j) carboxy, (k) acetyl, (1) dimethylcarbamoyl
and (m) dimethylsulphamoyl; and the remainder of R.sub.8 to R.sub.11 are
H,
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition as claimed in claim 6, wherein
n=0 or 1;
R.sub.1, R.sub.2, R.sub.6 and R.sub.7 are all H;
R.sub.3 and R.sub.4 are each H, or together are selected from the group
consisting of methylimino, phenylimino, hydroxyimino or methoxyimino;
R.sub.5 is H or methyl, or when R.sub.3 and R.sub.4 are each H, R.sub.5 is
selected from the group consisting of formyl, acetyl, propionyl, benzoyl,
methylsulphinyl, methylsulphonyl and ethylsulphonyl;
R.sub.8 is selected from the group consisting of H, methyl, fluoro and
chloro; and
R.sub.9 to R.sub.11 are all H,
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition as claimed in claim 6, wherein the compound
is selected from:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-fluoro-4-methylsulphonyl-2,3,4, 5-tetrahydro-1,4-benzothiazepine;
6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine; and
6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine,
a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition as claimed in claim 6, wherein the
compound is present in the composition in an amount from about 1 mg to
about 1000 mg.
11. A method of treating seizures in a patient in need of such treatment,
comprising administering to the patient a seizure-treating effective
amount of a pharmaceutical composition as claimed in claim 6.
12. A method as claimed in claim 11, wherein the pharmaceutical composition
is administered at a daily dose of from about 1 mg to about 5000 mg.
13. A method as claimed in claim 11, wherein the pharmaceutical composition
is administered at a daily dose of from about 5 mg to about 1000 mg.
14. A method of treating a neurological disorder in a patient in need of
such treatment, comprising administering to the patient a
neurological-disorder-treating effective amount of a pharmaceutical
composition as claimed in claim 6.
15. A method as claimed in claim 14, wherein the pharmaceutical composition
is administered at a daily dose of from about 1 mg to about 5000 mg.
16. A method as claimed in claim 14, wherein the pharmaceutical composition
is administered at a daily dose of from about 5 mg to about 1000 mg.
17. A method of treating epilepsy in a patient in need of such treatment,
comprising administering to the patient a epilepsy-treating effective
amount of a pharmaceutical composition as claimed in claim 6.
18. A method as claimed in claim 17, wherein the pharmaceutical composition
is administered at a daily dose of from about 1 mg to about 5000 mg.
19. A method as claimed in claim 17, wherein the pharmaceutical composition
is administered at a daily dose of from about 5 mg to about 1000 mg.
20. A method of neuroprotection in a patient in need of such protection,
comprising administering to the patient a neuroprotecting effective amount
of a pharmaceutical composition as claimed in claim 6.
21. A method as claimed in claim 20, wherein the pharmaceutical composition
is administered at a daily dose of from about 1 mg to about 5000 mg.
22. A method as claimed in claim 20, wherein the pharmaceutical composition
is administered at a daily dose of from about 5 mg to about 1000 mg.
23. A method of protecting against stroke in a patient in need of such
protection, comprising administering to the patient a stroke-protecting
effective amount of a pharmaceutical composition as claimed in claim 6.
24. A method as claimed in claim 23, wherein the pharmaceutical composition
is administered at a daily dose of from about 1 mg to about 5000 mg.
25. A method as claimed in claim 23, wherein the pharmaceutical composition
is administered at a daily dose of from about 5 mg to about 1000 mg.
26. A method of treating seizures in a patient in need of such treatment,
comprising administering to the patient a seizure-treating effective
amount of a compound as claimed in claim 1.
27. A method of treating a neurological disorder in a patient in need of
such treatment, comprising administering to the patient a
neurological-disorder-treating effective amount of a compound as claimed
in claim 1.
28. A method of treating epilepsy in a patient in need of such treatment,
comprising administering to the patient a epilepsy-treating effective
amount of a compound as claimed in claim 1.
29. A method of neuroprotection in a patient in need of such protection,
comprising administering to the patient a neuroprotecting effective amount
of a compound as claimed in claim 1.
30. A method of protecting against stroke in a patient in need of such
protection, comprising administering to the patient a stroke-protecting
effective amount of a compound as claimed in claim 1.
31. A process for preparing a compound as claimed in claim 1, comprising
reducing a compound of formula III
##STR9##
wherein n is 0, 1 or 2;
R.sub.1, R.sub.2, R.sub.6 and R.sub.7 are all H;
R.sub.5 is H;
R.sub.8 is selected from the group consisting of H, methyl, fluoro and
chloro; and
R.sub.9, R.sub.10 and R.sub.11 are each H,
a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
with a reducing agent to produce as a product a compound as claimed in
claim 1 wherein R.sub.3 and R.sub.4 are each H.
32. A process as claimed in claim 31, further comprising acylating the
product with an acid chloride, acid anhydride or acid to produce a
compound as claimed in claim 1 wherein R.sub.3 and R.sub.4 are each H, and
wherein R.sub.5 is a group of formula --COR.sub.13 wherein R.sub.13 is
selected from the group consisting of H, an alkyl of 1 or 2 carbon atoms
and phenyl.
Description
This application is a 371 of PCT/EP93/03123 filed Nov. 6, 1993. Priority is
also claimed of British applications GB 9223441.8 and GB 9223443.4, both
filed 9 Nov. 1992.
This invention relates to derivatives of
2,3,4,5-tetrahydro-1,4-benzothiazepines, to pharmaceutical compositions
containing them, to processes for their preparation and to their use in
the treatment of seizures and/or neurological disorders such as epilepsy
and/or as neuroprotective agents to protect against conditions such as
stroke.
In particular the present invention provides compounds of formula I
##STR2##
in which: n=0, 1 or 2
R.sub.1, R.sub.2, R.sub.6 and R.sub.7 independently represent H or alkyl of
1 to 4 carbon atoms (optionally substituted with one or more halo);
R.sub.3 and R.sub.4 independently represent H or alkyl of 1 to 4 carbon
atoms; or together represent a group of formula .dbd.NR.sub.12 where
R.sub.12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or
alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl and alkoxy being
optionally substituted with one or more halo;
R.sub.5 represents: (a) H, (b) alkyl of 1 to 4 carbon atoms, (c) a group of
formula --COR.sub.13 in which R.sub.13 represents H, alkyl of 1 to 4
carbon atoms or phenyl, when R.sub.3 and R.sub.4 represent H or alkyl
(optionally substituted with one or more halo), or (d) a group of formula
--S(O).sub.p R.sub.14 in which p=1 or 2 and R.sub.14 is alkyl of 1 to 4
carbon atoms or phenyl, when R.sub.3 and R.sub.4 represent H or alkyl
(optionally substituted with one or more halo); each alkyl and phenyl
being optionally substituted with one or more halo;
R.sub.8 to R.sub.11 independently represent H, halo, cyano, nitro, alkyl of
1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4
carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl
(optionally substituted with alkyl of 1 to 4 carbon atoms) or sulphamoyl
(optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl,
alkoxy, alkanoyl and alkanoyloxy being optionally substituted with one or
more halo;
their stereoisomers; and
pharmaceutically acceptable salts thereof;
with the provisos that:
(i) when n=0; at least one of R.sub.1 to R.sub.11 is other than H;
(ii) when n=0, 1 or 2; R.sub.1, R.sub.2 and R.sub.3 are independently H or
alkyl; R.sub.4 and R.sub.6 are both H; R.sub.5 is H, alkyl or alkanoyl;
and one of R.sub.8 or R.sub.9 and one of R.sub.9 to R.sub.10 are
separately H, halo, nitro, alkyl, alkoxy or trifluoromethyl, the remainder
of R.sub.8 to R.sub.11 being H; R.sub.7 is other than alkyl;
have utility in the treatment of seizures and/or neurological disorders
such as epilepsy and/or as neuroprotective agents to protect against
conditions such as stroke.
Compounds of formula I where n=0; R.sub.1 to R.sub.4, R.sub.6 to R.sub.8
and R.sub.11 are all H; R.sub.5 is H or acetyl; and R.sub.9 and R.sub.10
are both methoxy; are known from Szabo et al, Chem. Ber., 119, pages
2904-2913, (1986).
Compounds of formula I where n=0 or 2; R.sub.1 to R.sub.6, R.sub.8 and
R.sub.11 are all H; R.sub.7 is methyl; and R.sub.9 and R.sub.10 are both
methoxy; are known from J. Org. Chem., 30 (8), pages 2812-2818, (1965),
(Eng).
Compounds of formula I where n=0; R.sub.1, R.sub.2, R.sub.5, R.sub.6 and
R.sub.7 are all H; R.sub.3 is a straight chain alkyl of 1 to 4 carbon
atoms; R.sub.4 is a straight chain alkyl of 2 to 4 carbon atoms; and
R.sub.8 to R.sub.11 are independently H, halo, nitro, alkyl of 1 to 4
carbon atoms (optionally substituted by one or more halo) or alkoxy of 1
to 4 carbon atoms (optionally substituted by one or more halo); are known
as intermediates in the preparation of the compounds claimed in
International patent application WO 93/16055 (Wellcome) (see formula XIV,
page 18).
Compounds of formula I where n=0, 1 or 2; R.sub.1, R.sub.2 and R.sub.3 are
independently H or alkyl of 1 to 4 carbon atoms; R.sub.4 and R.sub.6 are
both H; R.sub.5 is H, alkyl of 1 to 4 carbon atoms or alkanoyl of 1 to 5
carbon atoms; R.sub.7 is alkyl of 1 to 4 carbon atoms and one of R.sub.8
or R.sub.9 and one of R.sub.10 or R.sub.11 are independently H, halo,
nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or
trifluoromethyl, the remainder of R.sub.8 to R.sub.11 being H; are known
from French patent application 4916-M (Hoffmann 1a Roche) (corresponding
inter alia to AU 409345) and are stated to have pharmaceutical activity as
anti-agconvulsants. The application does not contain any pharmaceutical
data to support this statement.
Compounds of formula I where n=0; R.sub.1 to R.sub.4, R.sub.6 to R.sub.8,
R.sub.10 and R.sub.11 are all H; R.sub.5 is H or bromoacetyl; and R.sub.9
is H or alkoxy of 1 to 3 carbon atoms; are known as intermediates in the
preparation of compounds claimed in International patent application WO
92/12143 (Kaneko) (see pages 4, 5 and 7) (corresponding to EP 0565721).
Compounds of formula I where n=0 or 1; R.sub.1 to R.sub.4, R.sub.6 and
R.sub.7 are independently H or alkyl of 1 to 4 carbon atoms; R.sub.5 is H,
alkyl of 1 to 4 carbon atoms or alkanoyl of 1 to 5 carbon atoms; and one
of R.sub.8 or R.sub.9 and one of R.sub.9 or R.sub.10 are separately H,
halo, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkanoyl of 1 to 5
carbon atoms or alkanoyloxy of 1 to 4 carbon atoms the remaining one of
R.sub.8 or R.sub.9 being H or chloro and the remaining one of R.sub.9 to
R.sub.10 being H; are known as Freidel Crafts catalysts from European
patent application 0368063 (Bayer) (claiming priority from DE 3837574 and
DE 3837575 and corresponding to US 4990707).
Compounds of formula I where n=0; R.sub.1 to R.sub.4 and R.sub.6 to
R.sub.11 are all H; and R.sub.5 is H or benzoyl; are known from Boudet et
al, C. R. Acad. Sci. Paris Series C, 282, pages 249-251 (26 Jan. 1976).
Compounds of formula I where n=0, R.sub.1 to R.sub.3 and R.sub.6 to
R.sub.11 are all H; R.sub.4 is H or methyl; and R.sub.5 is dichloroacetyl;
where n=1 or 2, R.sub.1 to R.sub.3 and R.sub.5 to R.sub.11 are all H and
R.sub.4 is H or methyl; and salts of compounds of formula I where n=1 or
2, R.sub.1 to R.sub.11 are all H; and the salt is hydrochloride salt; are
known from Indian J. Chem., 7(9), pages 862-5, (Eng) (in conjunction with
Chem. Abs., 71, 124391p, (1969) and Chem. Abs. 8th Coll. Subst. Ind.,
p4452S).
Therefore the present invention provides novel compounds of formula II
##STR3##
in which: n=0, 1 or 2; R.sub.1, R.sub.2, R.sub.6 and R.sub.7 independently
represent H or alkyl of 1 to 4 carbon atoms (optionally substituted with
one or more halo);
R.sub.3 and R.sub.4 independently represent H or alkyl of 1 to 4 carbon
atoms; or together represent a group of formula .dbd.NR.sub.12 where
R.sub.12 represents H, hydroxy, alkyl of 1 to 4 carbon atoms, phenyl or
alkoxy of 1 to 4 carbon atoms; each alkyl, phenyl and alkoxy being
optionally substituted with one or more halo;
R.sub.5 represents: (a) H, (b) alkyl of to 4 carbon atoms, (c) a group of
formula --COR.sub.13 in which R.sub.13 represents H, alkyl of 1 to 4
carbon atoms or phenyl, when R.sub.3 and R.sub.4 represent H or alkyl
(optionally substituted by one or more halo), or (d) a group of formula
--S(O).sub.p R.sub.14 in which p=1 or 2 and R.sub.14 is alkyl of 1 to 4
carbon atoms or phenyl, when R.sub.3 and R.sub.4 represent H or alkyl
(optionally substituted by one or more halo); each alkyl and phenyl being
optionally substituted with one or more halo;
R.sub.8 to R.sub.11 independently represent H, halo, cyano, nitro, alkyl of
1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkanoyl of 1 to 4
carbon atoms, carboxy, alkanoyloxy of 1 to 4 carbon atoms, carbamoyl
(optionally substituted with alkyl of 1 to 4 carbon atoms) or sulphamoyl
(optionally substituted with alkyl of 1 to 4 carbon atoms); each alkyl,
alkoxy, alkanoyl and alkanoyloxy being optionally substituted with one or
more halo;
their stereoisomers; and
pharmaceutically acceptable salts thereof;
with the provisos that:
(A) when n=0; R.sub.1 to R.sub.4, R.sub.6 to R.sub.8 and R.sub.11 are all
H; R.sub.5 is H or acetyl; and R.sub.9 is methoxy; R.sub.10 is other than
methoxy;
(B) when n=0 or 2; R.sub.1 to R.sub.6, R.sub.8 and R.sub.11 are all H;
R.sub.7 is methyl; and R.sub.9 is methoxy; R.sub.10 is other than methoxy;
(C) when n=0; R.sub.1, R.sub.2, R.sub.5, R.sub.6 and R.sub.7 are all H;
R.sub.3 is a straight chain alkyl; and R.sub.8 to R.sub.11 are
independently H, halo, nitro, alkyl (optionally substituted with one or
more halo) or alkoxy (optionally substituted with one or more halo);
R.sub.4 is other than a straight chain alkyl of 2 to 4 carbon atoms;
(D) when n=0, 1 or 2; R.sub.1, R.sub.2 and R.sub.3 are independently H or
alkyl; R.sub.4 and R.sub.6 are both H; R.sub.5 is H, alkyl or alkanoyl;
one of R.sub.8 or R.sub.9 and one of R.sub.10 to R.sub.11 are
independently H, halo, nitro, alkyl, alkoxy or trifluoromethyl, the
remainder of R.sub.8 to R.sub.11 being H; R.sub.7 is other than alkyl;
(E) when n=0; R.sub.1 to R.sub.4, R.sub.6 to R.sub.8 and R.sub.10 to
R.sub.11 are all H; and R.sub.5 is H or bromoacetyl; R.sub.9 is other than
H or alkoxy of 1 to 3 carbon atoms;
(F) when n=0 or 1; R.sub.1 to R.sub.4, R.sub.6 and R.sub.7 are
independently H or alkyl; and one of R.sub.8 or R.sub.9 and one of R.sub.9
or R.sub.10 are separately H, halo, cyano, nitro, alkyl, alkoxy, alkanoyl
or alkanoyloxy, the remaining one of R.sub.8 or R.sub.9 being H or chloro
and the remaining one of R.sub.9 to R.sub.10 being H; R.sub.5 is other
than H, alkyl or alkanoyl;
(G) when n=0; and R.sub.1 to R.sub.4 and R.sub.6 to R.sub.11 are all H;
R.sub.5 is other than H or benzoyl;
(H) when n=0; R.sub.1 to R.sub.3 and R.sub.6 to R.sub.11 are all H; and
R.sub.4 is H or methyl; R.sub.5 is other than dichloroacetyl; when n=1 or
2; and R.sub.1 to R.sub.3 and R.sub.5 to R.sub.11 are all H; R.sub.4 is
other than H or methyl; and when n=1 or 2; and R.sub.1 to R.sub.11 are all
H; the salt of compounds of formula I is other than a hydrochloride salt.
Preferred compounds of formula I or II are those in which (with the
provisos (i) and (ii) above):
n=0 or 1;
R.sub.1, R.sub.2, R.sub.6 and R.sub.7 are independently H or methyl;
R.sub.3 and R.sub.4 are independently H or methyl; or together represent
imino, methylimino, phenylimino, hydroxyimino or methoxyimino;
R.sub.5 is H or methyl, and when R.sub.3 and R.sub.4 are H or methyl,
R.sub.5 is formyl, acetyl, propionyl, benzoyl, methylsulphinyl,
methylsulphonyl or ethylsulphonyl; one of R.sub.8 to R.sub.11 is H,
fluoro, chloro, bromo, iodo, methyl (optionally substituted with one or
more halo), methoxy (optionally substituted by one or more halo),nitro,
cyano, carboxy, acetyl, dimethylcarbamoyl or dimethylsulphamoyl; the
remainder of R.sub.8 to R.sub.11 being H;
their stereoisomers; and
pharmaceutically acceptable salts thereof.
More preferred compounds of formula I or II are those in which (with the
provisos (i) and (ii) above):
n=0 or 1;
R.sub.1, R.sub.2, R.sub.6 and R.sub.7 are H; R.sub.3 and R.sub.4 are H; or
together are methylimino, phenylimino, hydroxyimino or methoxyimino;
R.sub.5 is H or methyl, and when R.sub.3 and R.sub.4 are H, R.sub.5 is
formyl, acetyl, propionyl, benzoyl, methylsulphinyl, methylsulphonyl or
ethylsulphonyl;
R.sub.8 is methyl, fluoro or chloro;
R.sub.9 to R.sub.11 are all H;
their stereoisomers; and
pharmaceutically acceptable salts thereof.
Specific compounds of formula I or II in which n=0 are:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4 -methyl -2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-acetyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine;
their stereoisomers; and
pharmaceutically acceptable salts thereof.
Specific compounds of formula I or II in which n=1 are:
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide;
their stereoisomers; and
pharmaceutically acceptable salts thereof.
It will be understood that a group containing a chain of three or more
carbon atoms may be straight or branched. The term `halo` as used herein
signifies fluoro, chloro, bromo or iodo.
Certain compounds of formula I or II may form salts with organic or
inorganic acids. Reference hereinafter to compounds of formula I or II
includes all such salts of compounds of formula I or II which are
pharmaceutically acceptable. Particularly suitable salts of compounds of
formula I or II include, for example, salts with inorganic acids, for
example hydrochlorides, hydrobromides, hydriodides, nitrates, sulphates
and phosphates, salts with organic acids, for example maleates, acetates,
citrates, fumarates, tartrates, succinates, benzoates, pamoates,
palmitates, methylsulphates, dodecanoates and salts with acidic amino
acids such as glutamic acid. It will be appreciated that such salts,
provided they are pharmaceutically acceptable, may be used in therapy in
place of the corresponding compounds of formula I or II. Such salts are
prepared by reacting the compound of formula I or II with a suitable acid
in a conventional manner.
Certain compounds of formula I or II or their salts may exist in more than
one crystal form and the present invention includes each crystal form and
mixtures thereof.
Certain compounds of formula I or II or their salts may also exist in the
form of solvates, for example hydrates, and the present invention includes
each solvate and mixtures thereof.
It will be appreciated by those skilled in the art that certain compounds
of formula I or II contain one or more chiral centres. Thus, for example
compounds of formula I or II in which n is 1 contain a chiral centre at
the sulphur atom; compounds of formula I or II in which R.sub.1 and
R.sub.2 are not identical contain a chiral centre at the 2-carbon atom;
compounds of formula I or II in which R.sub.3 and R.sub.4 are not
identical contain a chiral centre at the 3-carbon atom; and compounds of
formula I or II in which R.sub.6 and R.sub.7 are not identical contain a
chiral centre at the 5-carbon atom. A compound of formula I or II
containing a single chiral centre may exist in two enantiomeric forms. The
present invention includes each enantiomer of compounds of formula I or II
and mixtures thereof.
The enantiomers may be obtained by methods known to those skilled in the
art. Such methods typically include:
resolution via formation of diastereoisomeric salts or complexes which may
be separated, for example, by crystallisation;
formation of diastereoisomeric derivatives or complexes which may be
separated, for example, by crystallisation, gas-liquid chromatography or
liquid chromatography, followed by the liberation of the desired
enantiomer from the separated derivative;
selective derivatisation of one enantiomer by reaction with an
enantiomer-specific reagent, for example enzymatic esterification,
oxidation or reduction, followed by separation of the modified and
unmodified enantiomers; or
gas-liquid chromatography or liquid chromatography in a chiral environment,
for example on a chiral support such as silica with a bound chiral ligand,
or in the presence of a chiral solvent.
Alternatively, it may be possible to synthesise a specific enantiomer by
asymmetric synthesis using optically active reagents, substrates,
catalysts or solvents, or to convert one enantiomer into the other by
asymmetric transformation.
When a compound of formula I or II contains more than one chiral centre it
may exist in diastereoisomeric forms. The diastereoisomeric pairs may be
separated by methods known to those skilled in the art, for example
chromatography or crystallisation and the individual enantiomers within
each pair may be separated as described above. The present invention
includes each diastereoisomer of compounds of formula I or II and mixtures
thereof.
It will be appreciated that where the active moiety is transformed by the
separation procedures described above, a further step may be required to
convert the transformation product back to the active moiety.
Certain compounds of formula I or II may exist in different tautomeric
forms or as different geometric isomers, for example when R.sub.3 and
R.sub.4 together represent a group of formula .dbd.NR.sub.12. The present
invention includes each tautomer and/or geometric isomer and mixtures
thereof.
Certain compounds of formula I or II may exist in zwitterionic form and the
present invention includes each zwitterionic form and mixtures thereof.
The present invention also relates to pharmaceutical compositions
comprising a therapeutically effective amount of a compound of formula I
or II together with a pharmaceutically acceptable diluent or carrier. Such
pharmaceutical compositions may be used as neuroprotective agents to
protect against conditions such as stroke and/or for the treatment of
seizures and/or neurological disorders such as epilepsy. Specific
compounds which may be incorporated into the compositions of the present
invention are the compounds exemplified herein.
As used hereinafter, the term `active compound` denotes one or more
compound or compounds of formula I or II. In therapeutic use, the active
compound may be administered orally, rectally or parenterally, preferably
orally. Thus the therapeutic compositions of the present invention may
take the form of any of the known pharmaceutical compositions for such
methods of administration. The compositions may be formulated in a manner
known to those skilled in the art, to give a controlled release, for
example rapid release or sustained release, of the active compound.
Pharmaceutically acceptable carriers suitable for use in such compositions
are well known in the art of pharmacy. The compositions may contain from
about 0.1% to about 99% by weight of active compound and are generally
prepared in unit dosage form. Preferably the unit dosage of active
ingredient is from about 1 mg to about 1000 mg. The excipients used in the
preparation of these compositions are the excipients known in the
pharmacist's art.
Preferably the compositions of the invention are administered orally in the
known pharmaceutical forms for such administration. Dosage forms suitable
for oral administration may comprise tablets, pills, capsules, caplets,
granules, powders, elixirs, syrups, solutions and aqueous or oil
suspensions.
Solid oral dosage forms, for example tablets, may be prepared by mixing the
active compound with one or more of the following ingredients:
inert diluents, for example lactose, powdered sugar, pharmaceutical grade
starch, kaolin, mannitol, calcium phosphate or calcium sulphate;
disintegrating agents, for example maize starch, methyl cellulose, agar,
bentonite, cellulose, wood products, alginic acid, guar gum, citrus pulp,
carboxymethylcellulose or sodium lauryl sulphate;
lubricating agents, for example magnesium stearate, boric acid, sodium
benzoate, sodium acetate, sodium chloride, leucine or polyethylene glycol;
binders, for example starch, gelatin, sugars (such as sucrose, molasses or
lactose), or natural and synthetic gums (such as acacia, sodium alginate,
extract of Irish moss, carboxymethylcellulose, methylcellulose,
ethylcellulose, polyethylene glycol, waxes, microcrystalline cellulose or
polyvinylpyrrolidone);
colouring agents, for example conventional pharmaceutically acceptable
dyes;
sweetening and flavouring agents;
preservatives; and
other optional ingredients known in the art to permit production of oral
dosage forms by known methods such as tabletting.
Solid oral dosage forms may be formulated in a manner known to those
skilled in the art so as to give a sustained release of the compounds of
the present invention. For example tablets or pills may, if desired, be
provided with enteric coatings by known methods, for example by the use of
cellulose acetate phthalate and/or hydroxypropylmethylcellulose phthalate.
Capsules or caplets, for example hard or soft gelatin capsules, containing
the active compound with or without added excipients, for example a fatty
oil, may be prepared by conventional means and, if desired, provided with
enteric coatings in a known manner. The contents of the capsule or caplet
may be formulated using known methods to give sustained release of the
active compound. Enteric coated, solid oral dosage forms comprising
compositions of the invention may be advantageous, depending on the nature
of the active compound. Various materials, for example shellac and/or
sugar, may be present as coatings, or to otherwise modify the physical
form of the oral dosage form.
Liquid oral dosage forms comprising compositions of the invention may be
elixirs, solutions, suspensions or syrups, for example, aqueous
suspensions containing the active compound in an aqueous medium in the
presence of a non-toxic suspending agent such as sodium
carboxymethylcellulose; or oily suspensions containing a compound of the
present invention in a suitable vegetable oil, for example arachis oil or
sunflower oil. Liquid oral dosage forms may also comprise sweetening
agents, flavouring agents and/or preservatives.
The active compound may be formulated into granules or powders with or
without additional excipients. The granules or powders may be ingested
directly by the patient or they may be added to a suitable liquid carrier
(for example water) before ingestion. The granules or powders may contain
disintegrants (for example a pharmaceutically acceptable effervescent
couple formed from an acid and a carbonate or bicarbonate salt) to
facilitate dispersion in the liquid medium.
Each of the above oral dosage forms may conveniently contain from about 1
mg to about 1000 mg of the active compound.
Compositions of the invention may be administered rectally in the known
pharmaceutical forms for such administration, for example, suppositories
with hard fat, semi-synthetic glyceride, cocoa butter or polyethylene
glycol bases.
Compositions of the invention may also be administered parenterally, for
example by intravenous injection, in the known pharmaceutical forms for
such administration, for example sterile suspensions in aqueous or oily
media, or sterile solutions in a suitable solvent.
The active compound may also be administered by continuous infusion either
from an external source, for example by intravenous infusion, or from a
source of the compound placed within the body. Internal sources include
implanted reservoirs containing the compound to be infused which is
continuously released (for example by osmosis) or implants. Implants may
be liquid, such as a suspension or solution in a pharmaceutically
acceptable oil of the compound to be infused (for example in the form of a
very sparingly water-soluble derivative such as a dodecanoate salt or
ester). Implants may be solid in the form of an implanted support (for
example a synthetic resin or waxy material) for the compound to be
infused. The support may be a single body containing all the compound or a
series of several bodies each containing part of the compound to be
delivered. The amount of active compound present in an internal source
should be such that a therapeutically effective amount of the compound is
delivered over a long period of time.
In some formulations it may be beneficial to use the active compound, or
pharmaceutical compositions containing the active compound, in the form of
particles of very small size, for example as obtained by fluid energy
milling.
In the above compositions the active compound may, if desired, be
associated with other compatible pharmacologically active ingredients.
A further aspect of the present invention provides use of compounds of
formula I or II in the preparation of a medicament for the treatment of
seizures and/or neurological disorders such as epilepsy and/or for
neuroprotection to protect against conditions such as stroke.
A still further aspect of the present invention provides a method of
treating seizures and/or neurological disorders such as epilepsy and/or a
method of neuroprotection to protect against conditions such as stroke,
which comprises the administration to patient in need thereof a
therapeutically effective amount of compounds of formula I or II and/or a
pharmaceutical compositions containing a therapeutically effective amount
of compounds of formula I or II. Thus compounds of formula I or II are
useful for the inhibition of seizures and/or neurological disorders such
as epilepsy and/or as neuroprotective agents to protect against conditions
such as stroke.
Whilst the precise amount of the active compound administered in the
treatments outlined above will depend on a number of factors, for example
the severity of the condition, the age and past medical history of the
patient, and always lies within the sound discretion of the administering
physician, a suitable daily dose of compounds of formula I or II for
administration to human beings, is generally from about 1 mg to about 5000
mg, more usually from about 5 mg to about 1000 mg, given in a single dose
or in divided doses at one or more times during the day. Oral
administration is preferred.
Compounds of formula I or II may be used in adjunctive therapy with one or
more other compounds having activity in the treatment of seizures and/or
neurological disorders such as epilepsy and/or as neuroprotective agents
to protect against conditions such as stroke. It will be appreciated that
the term therapy as used herein includes prophylactic use of compounds of
formula I or II and pharmaceutical compositions containing compounds of
formula I or II, for example as neuroprotective agents to protect against
conditions such as stroke or to prevent the onset of epileptic seizures.
Compounds of formula I or II and pharmaceutical compositions containing
compounds of formula I or II may be used to provide a local and/or
systemic therapeutic effect.
The therapeutic activity of compounds of formula I or II has been
demonstrated by means of tests in standard laboratory animals. Such tests
include, for example, the tests of anticonvulsant activity in mice
described below.
Processes for the preparation of compounds of formula I or II will now be
described. These processes form a further aspect of the present invention.
Compounds of formula I or II, in which R.sub.3 and R.sub.4 are both H and
R.sub.5 is H or alkyl may be prepared by reducing a compound of formula
III
##STR4##
in which R.sub.5 is H or alkyl, with a reducing agent, for example lithium
aluminium hydride or borane-dimethyl-sulphide complex. Compounds of
formula III are known and can be prepared as described in international
patent application WO 92/21668.
Compounds of formula I or II in which R.sub.3 and R.sub.4 together are a
group of formula .dbd.NR.sub.12 may be prepared by the reaction of
compounds of formula IV
##STR5##
with a compound of formula R.sub.12 NH.sub.2.
Compounds of formula I or II in which R.sub.3 and R.sub.4 together are a
group of formula .dbd.NR.sub.12 and R.sub.5 is H may be prepared by the
reaction of compounds of formula V
##STR6##
with a compound of formula R.sub.12 NH.sub.2.
Compounds of formula I or II in which R.sub.3 and R.sub.4 together are
alkoxyimino may be prepared by the reaction between compounds of formula I
or II in which R.sub.3 and R.sub.4 together are hydroxyimino with an
alkylating agent such as an alkylsulphate.
Compounds of formula I or II in which R.sub.3 and R.sub.4 are H or alkyl
and R.sub.5 is alkyl may be prepared by alkylation of compounds of formula
I or II in which R.sub.5 is H for example; by using an alkylating agent
such as an alkyl halide; or by reductive alkylation with an aldehyde or a
ketone and formic acid, or a reducing agent such as sodium
cyanoborohydride; or by reducing a compound of formula I or II in which
R.sub.5 is a group of formula --COR.sub.13.
Compounds of formula I or II in which R.sub.5 is a group of formula
--COR.sub.13 may be prepared by acylation of compounds of formula I or II
in which n=0 or 2 and R.sub.5 is H, for example with an acid chloride of
formula R.sub.13 COCl, an acid anhydride of formula (R.sub.13 CO).sub.2 O
or an acid of formula R.sub.13 CO.sub.2 H.
Compounds of formula I or II in which R.sub.5 is a group of formula
--S(O).sub.p R.sub.14 may be prepared by the reaction of compounds of
formula I or II in which R.sub.5 is H, with a sulphonylating agent such as
a sulphonyl chloride of formula R.sub.14 SO.sub.2 Cl, or a sulphinylating
agent such as a sulphinyl chloride of formula R.sub.14 SOCl. For example,
compounds of formula I or II in which R.sub.5 is --SO.sub.2 Me may be
prepared by the reaction of a compound of formula I or II in which R.sub.5
is H with methanesulphonyl chloride.
Compounds of formula I or II in which n=1 may be prepared by the oxidation
of compounds of formula I or II in which n=0, for example using sodium
periodate or 3-chloroperbenzoic acid.
Compounds of formula I or II in which n=2 may be prepared by the oxidation
of compounds of formula I or II in which n=0 or 1, for example using
peracetic acid or 3-chloroperbenzoic acid.
Compounds of formula IV may be prepared by the reaction of compounds of
formula III with reagents such as phosphorus pentasulphide or Lawesson's
reagent [which is the known compound
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4 disulphide].
Compounds of formula V may be prepared by the reaction of compounds of
formula III with a chlorinating agent, for example phosphorus
pentachloride or phosphoryl chloride.
The anticonvulsant activity of compounds of formula I or II was
demonstrated by the following pharmacological tests.
Firstly, by observing the ability of the compound of formula I or II to
antagonise the myoclonic seizures induced by the administration of
(+)-bicuculline. Hereinafter, this test is referred to as `BICM`.
In the BICM experiments groups of female mice in the weight range 25 to 30
grammes had free access to food and water until one hour before
administration of the compound of formula I or II to be tested. The
compound to be tested was orally administered at one or more doses in 1%
aqueous methylcellulose solution. One hour later (+)-bicuculline at a dose
of 0.55 mg/kg was administered intravenously into a tail vein. Such a dose
of (+)-bicuculline would generally be expected to induce a seizure in the
mice.
During the following two minutes the animals were observed and the
percentage of animals in which seizures had been inhibited was recorded.
Thus, the greater the anticonvulsant activity of the compound, the higher
was the percentage recorded in the BICM test. If results at more than one
dose were available, then a value for the dose inhibiting the seizures in
50% of the animals (ED.sub.50) was calculated from the regression straight
line plot of the percentage of animals in which seizures were inhibited
against the dose of the compound of formula I or II administered.
The second test of anticonvulsant activity involved observing the ability
of a compound to inhibit seizures in mice induced by a maximal
electroshock. Hereinafter, this test is referred to as `MESM`.
In the MESM experiments, groups of male mice in the weight range 25 to 30
grammes had free access to food and water until one hour before
administration of the compound of formula I or II to be tested. The
compound to be tested was orally administered at one or more doses in 1%
aqueous methylcellulose solution. One hour later an electroshock of
duration 1.0 second was administered to the mice through ear clip
electrodes. The electroshock had an intensity of 99 mA, frequency of 50 Hz
and pulse width of 0.4 ms. Such a shock would generally be expected to
induce a seizure in the mice.
During the following two minutes the animals were observed and the
percentage of animals in which seizures had been inhibited was recorded.
Thus, the greater the anticonvulsant activity of the compound, the higher
was the percentage recorded in the MESM test. If results at more than one
dose were available, then a value for the dose inhibiting seizures in 50%
of the animals (ED.sub.50) was calculated from the regression straight
line plot of the percentage of animals in which seizures were inhibited
against the dose of the compound of formula I or II administered.
The compounds of formula I or II described hereinafter in Examples 1 to 31
have been found to have anticonvulsant activity in at least one of the
BICM and MESM tests.
The invention will now be illustrated by the following non-limiting
examples. The final product of each example was characterised by one or
more of the following; elemental analysis; infra-red spectroscopy; nuclear
magnetic resonance spectroscopy; and/or liquid chromatography.
Temperatures are given in degrees Celsius.
EXAMPLE 1
6-Chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (9.8 g, prepared in a
similar manner to example 11 of international patent application WO
92/21668) was added to a stirred solution of lithium aluminium hydride
(5.01 g) in dry tetrahydrofuran (400 ml), After the addition, the reaction
mixture was heated under reflux for five minutes and cooled. Excess
lithium aluminium hydride was decomposed by adding a saturated aqueous
solution of sodium sulphate. The mixture was filtered and the solvent
removed from the filtrate by evaporation. The residue was dissolved in
diethyl ether, acidified with hydrogen chloride gas and the precipitated
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride was
collected by filtration, and was recrystallised from ethanol. Yield 6.5 g
(m.p. 244.degree.-246.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 8.2
mg/kg.
EXAMPLE 2
6-Chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (9.8 g, prepared in a
similar manner to example 11 of international patent application WO
92/21668) was added to a stirred solution of lithium aluminium hydride
(5.01 g) in dry tetrahydrofuran (400 ml). After the addition, the reaction
mixture was heated under reflux for five minutes and then cooled. Excess
lithium aluminium hydride was decomposed by adding of a saturated aqueous
solution of sodium sulphate. The mixture was filtered and the solvent
evaporated from the filtrate to give
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil.
A solution of sodium periodate (3.09 g) in water (25 ml) was added dropwise
with cooling to a stirred solution of
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.88 g, prepared in a
similar manner to that described in the preceding paragraph) in
dichloromethane (75 ml). The stirring was continued at room temperature
for 19 hours. Solvent was removed from the mixture by evaporation at
reduced pressure. Purification of the residue by flash chromatography
using dichloromethane/ethanol (95:5) as eluent gave
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was
recrystallised from ethyl acetate. Yield 2.15 g (m.p.
125.degree.-126.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 2.7
mg/kg.
EXAMPLE 3
6-Fluoro-4,5-dihydro-1,4-benzothiazepin-3 (2H) -one (9 g, prepared in a
similar manner to example 5 of international patent application WO
92/21668) was added to a stirred solution of lithium aluminium hydride (5
g) in dry tetrahydrofuran (500 ml). After the addition, the reaction
mixture was heated under reflux for ten minutes and cooled. Excess lithium
aluminium hydride was decomposed by adding a saturated aqueous solution of
sodium sulphate. The mixture was filtered and the solvent removed from the
filtrate by evaporation to give an oil, which was dissolved in diethyl
ether and acidified with hydrogen chloride gas. The precipitated
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride was
collected by filtration and was recrystallised from ethanol. Yield 7.43 g
(m.p. 265.degree.-68.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 17.7
mg/kg.
EXAMPLE 4
6-Methyl-4,5-dihydro-1,4-benzothiazepin-3 (2H) -one (6 g, prepared in a
similar manner to example 13 of international patent application WO
92/21668) was added to a stirred solution of lithium aluminium hydride
(3.38 g) in dry tetrahydrofuran (340 ml). After the addition, the reaction
mixture was heated under reflux for ten minutes, and cooled. Excess
lithium aluminium hydride was decomposed by adding a saturated aqueous
solution of sodium sulphate. The mixture was filtered and the solvent was
removed from the filtrate by evaporation. The residue was dissolved in
diethyl ether, acidified with hydrogen chloride gas and the precipitated
6-methyl-2,3,4,5-tetrahydro-1-1,4-benzothiazepine hydrochloride was
collected by filtration and was recrystallised from ethanol. Yield 2.87 g
(m.p. 248.degree.-250.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 66.5
mg/kg.
EXAMPLE 5
A solution of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (5.33 g,
prepared in a similar manner to example 11 of international patent
application WO 92/21668) in dry dimethylsulphoxide (60 ml) was added
slowly at room temperature to a stirred suspension of sodium hydride (0.6
g) in dimethylsulphoxide (20 ml). After the addition was completed, the
mixture was stirred for 30 minutes before adding methyl iodide (6 ml)
dropwise. The reaction mixture was stirred at room temperature for one
hour, water (160 ml) was added and the mixture was extracted with diethyl
ether. The organic layer was washed with water and the solvent was removed
by evaporation. Purification of the residue by flash chromatography using
dichloromethane/ethyl acetate (9.8:0.2) as eluent gave
6-chloro-4-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-one. Yield 3.8 g
(m.p. 122.degree.-125.degree. C.).
6-Chloro-4-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (3.8 g) was
added to a stirred solution of lithium aluminium hydride (1.92 g) in dry
tetrahydrofuran (160 ml). After the addition, the reaction was heated
under reflux for 15 minutes and cooled. Excess lithium aluminium hydride
was decomposed by adding a saturated aqueous solution of sodium sulphate.
The mixture was filtered and the solvent was removed from the filtrate by
evaporation. Purification of the residue by flash chromatography using
dichloromethane/ethanol (9.5:0.5) as eluent gave an oil (2.62 g) which was
dissolved in diethyl ether and acidified with hydrogen chloride gas. The
precipitated 6-chloro-4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine
hydrochloride was collected by filtration and was recrystallised from
ethanol/diethyl ether. Yield 2.38 g (m.p. 209.degree.-211.degree. C.).
In the BICM test described above, a dosage of 100 mg/kg of this compound
inhibited 50% of the mice tested from seizures.
EXAMPLE 6
4,5-Dihydro-1,4-benzothiazepin-3(2H)-one (12 g, prepared in a similar
manner to example 1 of international patent application WO 92/21668) was
added to a stirred solution of lithium aluminium hydride (6.3 g) in dry
tetrahydrofuran (400 ml). After the addition, the reaction mixture was
heated under reflux for ten minutes and cooled. Excess of lithium
aluminium hydride was decomposed by adding a saturated aqueous solution of
sodium sulphate. The mixture was filtered and the solvent was removed from
the filtrate by evaporation to give 2,3,4,5-tetrahydro-1,4-benzothiazepine
as an oil which was used without further purification. Yield 9.4 g.
A mixture of 2,3,4,5-tetrahydro-1,4-benzothiazepine (4.56 g), formic acid
(20 ml) and toluene (60 ml) was heated under reflux at 90.degree. C. for
four hours and then at 120.degree. C. for a further three hours. The
solvent was removed from the mixture by evaporation at reduced pressure.
Purification of the residue by flash chromatography using dichloromethane
as eluent gave 4-formyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from hexane. Yield 3.73 g (m.p. 84.degree.-87.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 17.9
mg/kg.
EXAMPLE 7
A solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (1.5 g, prepared as
described in the first paragraph of Example 6 above) in acetic anhydride
(15 ml) was stirred at room temperature for one hour. The reaction mixture
was poured into ice and extracted with dichloromethane. The organic layer
was dried and the solvent removed by evaporation to give
4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine [a compound known as a
Friedel Crafts catalyst from Example 46 of EP 368063 (Bayer)]. The product
was recrystallised from hexane. Yield 1.55 g (m.p. 69.degree.-70.degree.
C.).
The ED.sub.50, in the BICM test described above, for this compound was 65.7
mg/kg.
EXAMPLE 8
A solution of 3-chloroperbenzoic acid (1.03 g) in dichloromethane (100 ml)
was added dropwise with cooling from 0.degree. C. to -2.degree. C. to a
stirred solution of 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.03
g, prepared as Example 7 above) in dichloromethane (50 ml). The reaction
mixture was stirred for 15 minutes, then washed with water, dried and the
solvent was removed by evaporation at reduced pressure. Purification of
the residue by flash chromatography using dichloromethane/ethanol (9:1) as
eluent gave 4-acetyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which
was recrystallised from ethyl acetate. Yield 0.67 g (m.p.
156.degree.-157.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 37.8
mg/kg.
EXAMPLE 9
A solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.6 g,
prepared in a similar manner to its hydrochloride, Example 1 above) in
acetic anhydride (15 ml) was stirred at room temperature for one hour. The
reaction mixture was poured into ice and extracted with dichloromethane.
The organic layer was dried and the solvent was removed by evaporation to
give 4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from hexane. Yield 1.68 g (m.p. 79.degree.-81.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 4.6
mg/kg.
The ED.sub.50, in the MESM test described above, for this compound was 48.5
mg/kg.
EXAMPLE 10
A solution of 3-chloroperbenzoic acid (1.14 g) in dichloromethane (100 ml)
was added dropwise with cooling from 0.degree. C. to -2.degree. C. to a
stirred solution of
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.34 g, prepared
as Example 9 above) in dichloromethane (50 ml). The reaction mixture was
stirred for 15 minutes, washed with water, dried and the solvent was
removed by evaporation at reduced pressure. Purification of the residue by
flash chromatography using dichloromethane/ethanol (95:5) as eluent gave
4-acetyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which
was recrystallised from ethyl acetate. Yield 1.15 g (m.p.
119.degree.-121.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 22.6
mg/kg.
The ED.sub.50, in the MESM test described above, for this compound was 52.8
mg/kg.
EXAMPLE 11
A solution of 6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.04 g,
prepared in a similar manner to its hydrochloride, Example 3 above) in
acetic anhydride (22 ml) was stirred at room temperature for one hour. The
reaction mixture was poured into ice and extracted with dichloromethane.
The organic layer was dried and the solvent removed by evaporation.
Purification of the residue by flash chromatography using
dichloromethane/ethanol (97:3) as eluent gave
4-acetyl-6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine as an oil. Yield
1.7 g.
The ED.sub.50, in the BICM test described above, for this compound was 21.5
mg/kg.
EXAMPLE 12
A solution of 6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.91 g,
prepared in a similar manner to its hydrochloride, Example 4 above) in
acetic anhydride (10 ml) was stirred at room temperature for one hour. The
reaction mixture was poured into ice and extracted with dichloromethane.
The organic layer was dried and the solvent removed by evaporation to give
4-acetyl-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from hexane. Yield 0.93 g (m.p. 71.degree.-73.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 49.4
mg/kg.
In the MESM test described above, a dosage of 100 mg/kg of this compound
inhibited 50% of the mice tested from seizures.
EXAMPLE 13
A solution of propionyl chloride (2.39 g) in dichloromethane (50 ml) was
added dropwise at room temperature to a stirred solution of
2,3,4,5-tetrahydro-1,4-benzothiazepine (8.58 g, prepared as described in
the first paragraph of Example 6 above) in dichloromethane (100 ml). The
reaction mixture was stirred at room temperature for 45 minutes, washed
with water, dried and the solvent was removed by evaporation. Purification
of the residue by flash chromatography using dichloromethane/ethanol
(98:2) as eluent gave 4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine
as an oil. Yield 2.9 g.
The ED.sub.50, in the BICM test described above, for this compound was 48.1
mg/kg.
EXAMPLE 14
A solution of propionyl chloride (0.92 g) in dichloromethane (10 ml) was
added dropwise at room temperature to a stirred solution of
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in a
similar manner to its hydrochloride, Example 1 above) and triethylamine
(1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred at
room temperature for 30 minutes, washed with water, dried and the solvent
was removed by evaporation. Purification of the residue by flash
chromatography using dichloromethane as eluent gave
6-chloro-4-propionyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from hexane. Yield 1.14 g (m.p. 55.degree.-57.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 44.7
mg/kg.
EXAMPLE 15
A solution of benzoyl chloride (3.93 g) in dichloromethane (50 ml) was
added dropwise at room temperature to a stirred solution of
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (4.5 g, prepared in a
similar manner to its hydrochloride, Example 1 above) and triethylamine
(2.82 g) in dichloromethane (100 ml). The reaction mixture was stirred at
room temperature for 15 minutes, washed with water, dried and the solvent
was removed by evaporation. Purification of the residue by flash
chromatography using dichloromethane as eluent gave
4-benzoyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from ethanol/water. Yield 5.93 g (m.p.
64.degree.-72.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 49.2
mg/kg.
EXAMPLE 16
A solution of methanesulphinyl chloride (0.98 g) in dichloromethane (10 ml)
was added dropwise at room temperature to a stirred solution of
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in a
similar manner to its hydrochloride, Example 1 above) and triethylamine
(1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred at
room temperature for one hour, washed with water, dried and the solvent
was removed by evaporation. Purification of the residue by flash
chromatography using dichloromethane/ethanol (98:2) as eluent gave
6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which
was recrystallised from ethylacetate/hexane. Yield 2.1 g (m.p.
82.degree.-84.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 19.6
mg/kg.
EXAMPLE 17
A solution of methanesulphonyl chloride (3.3 g) in dichloromethane (15 ml)
was added dropwise at room temperature to a stirred solution of
2,3,4,5-tetrahydro-1,4-benzothiazepine (4.8 g, prepared as described in
the first paragraph of Example 6 above) and triethylamine (2.9 g) in
dichloromethane (100 ml). The reaction mixture was stirred at room
temperature for one hour, washed with water, dried and the solvent was
removed by evaporation. Purification of the residue by flash
chromatography using dichloromethane as eluent gave
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine which was
recrystallised from hexane. Yield 3 g. (m.p. 98.degree.-100.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 40.8
mg/kg.
The ED.sub.50, in the MESM test described above, for this compound was 51.6
mg/kg.
EXAMPLE 18
A solution of 3-chloroperbenzoic acid (1.4 g) in dichloromethane (200 ml)
was added dropwise with cooling from 0.degree. C. to -2.degree. C. to a
stirred solution of
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (2 g, prepared as
Example 17 above) in dichloromethane (50 ml). The reaction mixture was
stirred for 15 minutes, washed with water, dried and the solvent was
removed by evaporation at reduced pressure. Purification of the residue by
flash chromatography using dichloromethane/ethanol (95:5) as eluent gave
4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which
was recrystallised from ethanol. Yield 1.65 g (m.p.
195.degree.-197.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 27.4
mg/kg.
EXAMPLE 19
A solution of methanesulphonyl chloride (3.43 g) in dichloromethane (30 ml)
was added dropwise at room temperature to a stirred solution of
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (5.2 g, prepared in a
similar manner to its hydrochloride, Example 1 above) and triethylamine
(3.03 g, 0.03 ml) in dichloromethane (100 ml). The reaction mixture was
stirred at room temperature for one hour, washed with water, dried and the
solvent was removed by evaporation. Purification of the residue by flash
chromatography using dichloromethane as eluent gave
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which
was recrystallised from hexane. Yield 6.06 g (m.p. 85.degree.-86.degree.
C.).
The ED.sub.50, in the BICM test described above, for this compound was 41.3
mg/kg.
The ED.sub.50, in the MESM test described above, for this compound was 19.5
mg/kg.
EXAMPLE 20
A solution of 3-chloroperbenzoic acid (2.26 g) in dichloromethane (150 ml)
was added dropwise with cooling from 0.degree. C. to -2.degree. C. to a
stirred solution of
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (3.05 g,
prepared as Example 19 above) in dichloromethane (100 ml). The reaction
mixture was stirred for 15 minutes, washed with water and dried, and the
solvent was removed by evaporation at reduced pressure. Purification of
the residue by flash chromatography using dichloromethane/ethanol (95:5)
as eluent gave
6-chloro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide,
which was recrystallised from ethyl acetate. Yield 2.86 g (m.p.
167.degree.-169.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 36.2
mg/kg.
The ED.sub.50, in the MESM test described above, for this compound was 31.9
mg/kg.
EXAMPLE 21
A solution of methanesulphonyl chloride (1.83 g) in dichloromethane (30 ml)
was added dropwise at room temperature to a stirred solution of
6-fluoro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.65 g, prepared in a
similar manner to its hydrochloride, Example 3 above) and triethylamine
(1.6 g) in dichloromethane (60 ml). The reaction mixture was stirred at
room temperature for 20 minutes, washed with water, dried and the solvent
was removed by evaporation. Purification of the residue by flash
chromatography using dichloromethane as eluent gave
6-fluoro-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which
was recrystallised from hexane. Yield 3.3 g (m.p. 115.degree.-117.degree.
C.).
The ED.sub.50, in the BICM test described above, for this compound was 33.8
mg/kg.
The ED.sub.50, in the MESM test described above, for this compound was 30.5
mg/kg.
EXAMPLE 22
A solution of methanesulphonyl chloride (1.69 g) in dichloromethane (20 ml)
was added dropwise at room temperature to a stirred solution to
6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (2 g, prepared in a
similar manner to its hydrochloride, Example 4 above) and triethylamine
(1.51 g) in dichloromethane (30 ml). The reaction mixture was stirred at
room temperature for one hour, washed with water, dried and the solvent
was removed by evaporation. Purification of the residue by flash
chromatography using dichloromethane as eluent gave
6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which
was recrystallised from ethyl acetate/hexane. Yield 2.48 g (m.p.
128.degree.-130.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was
116.3 mg/kg.
The ED.sub.50, in the MESM test described above, for this compound was
102.2 mg/kg.
EXAMPLE 23
A solution of ethanesulphonyl chloride (3.8 g) in dichloromethane (50 ml)
was added dropwise at room temperature to a stirred solution of
2,3,4,5-tetrahydro-1,4-benzothiazepine (4.29 g, prepared as described in
the first paragraph of Example 6 above) in dichloromethane (100 ml). The
reaction mixture was stirred at room temperature for one hour, washed with
water, dried and the solvent was removed by evaporation. Purification of
the residue by flash chromatography using trichloromethane as eluent gave
4-ethylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from hexane. Yield 4.25 g (m.p. 78.degree.-80.degree. C.).
The ED.sub.50, in the MESM test described above, for this compound was 22.3
mg/kg.
EXAMPLE 24
A solution of ethanesulphonyl chloride (1.28 g) in dichloromethane (10 ml)
was added dropwise at room temperature to a stirred solution of
6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in a
similar manner to its hydrochloride, Example 1 above) and triethylamine
(1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred at
room temperature for one hour, washed with water, dried and the solvent
was removed by evaporation. Purification of the residue by flash
chromatography using dichloromethane as eluent gave
4-ethylsulphonyl-6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine, which
was recrystallised from ethyl acetate/hexane. Yield 2.53 g (m.p.
126.degree.-128.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 90.4
mg/kg.
The ED.sub.50, in the MESM test described above, for this compound was 35.1
mg/kg.
EXAMPLE 25
A stirred mixture of 4,5-dihydro-1,4-benzothiazepin-3(2H)-one (1.79 g,
prepared as example 1 of international patent application WO 92/21668) and
Lawesson's reagent (2.22 g) in dry toluene (100 ml) was heated at
100.degree. C. for three hours. The mixture was allowed to cool to room
temperature. The precipitated solid was collected by filtration, washed
with toluene and dried to give
4,5-dihydro-1,4-benzothiazepin-3(2H)-thione. Yield 1.78 g (m.p.
215.degree.-219.degree. C.).
A mixture of 4,5-dihydro-1,4-benzothiazepin-3(2H)-thione (1.56 g),
hydroxylamine hydrochloride (0.83 g) and sodium acetate (0.98 g) in dry
ethanol (100 ml) was heated under reflux for three hours. The mixture was
cooled, and the precipitated solid was collected by filtration and washed
with water. Purification of the precipitate by flash chromatography using
dichloromethane/ethanol (95:5) as eluent gave
3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from ethanol. Yield 1.2 g (m.p. 208.degree.-210.degree.
C.).
The ED.sub.50, in the BICM test described above, for this compound was 31.5
mg/kg.
EXAMPLE 26
A stirred mixture of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one
(4.27 g, prepared as example 11 of international patent application WO
92/21668) and Lawesson's reagent (4.90 g) in dry toluene (170 ml) was
heated under reflux for one hour. The reaction mixture was cooled to room
temperature and the precipitated
6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-thione was collected by
filtration, washed with toluene and dried. Yield 4.16 g (m.p.
210.degree.-212.degree. C.).
A stirred mixture of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-thione
(3.90 g), hydroxylamine hydrochloride (1.77 g) and sodium acetate (2.09 g)
in dry ethanol (175 ml) was heated under reflux for one hour. The reaction
mixture was cooled and the precipitated
6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine was
collected by filtration, washed with water and recrystallised from
ethanol. Yield 2.6 g (m.p. 180.degree.-183.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 5.0
mg/kg.
EXAMPLE 27
A stirred mixture of 6-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-one
(3.26 g, prepared in a similar manner to example 13 of international
patent application WO 92/21668) and Lawesson's reagent (3.93 g) in dry
toluene (170 ml) was heated under reflux for one hour. The reaction
mixture was cooled to room temperature and the precipitated
6-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-thione was collected by
filtration, washed with toluene and dried. Yield 3.30 g (m.p.
228.degree.-230.degree. C.).
A stirred mixture of 6-methyl-4,5-dihydro-1,4-benzothiazepin-3(2H)-thione
(3.13 g), hydroxylamine hydrochloride (1.56 g) and sodium acetate (1.84 g)
in dry ethanol (175 ml) was heated under reflux for one hour. The reaction
mixture was cooled and the precipitated
3-hydroxyimino-6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine was
collected by filtration, washed with water and recrystallised from
ethanol. Yield 2.23 g (m.p. 188.degree.-190.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 20.1
mg/kg.
EXAMPLE 28
Dimethylsulphate (1.26 g) was added dropwise to a vigorously stirred
suspension of 3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine (2 g,
prepared in a similar manner to Example 25 above) in a mixture of a 10%
aqueous solution of sodium hydroxide (4 ml) and ethanol (150 ml). The
reaction mixture was kept at room temperature for 24 hours and then
extracted with dichloromethane. The organic layer was dried and the
solvent was removed by evaporation. Purification of the solid residue by
flash chromatography using dichloromethane as eluent gave
3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from hexane. Yield 1.51 g (m.p. 101.degree.-102.degree.
C.).
The ED.sub.50, in the BICM test described above, for this compound was 58.2
mg/kg.
EXAMPLE 29
A 10% aqueous solution of sodium hydroxide (4 ml) was added to a suspension
of 6-chloro-3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.29 g,
prepared as Example 26 above) in ethanol (150 ml). After 15 minutes
dimethylsulphate (1.33 g) was added dropwise to the mixture. The reaction
mixture was stirred at room temperature for 22 hours and then the solvent
was removed by evaporation at reduced pressure. Purification of the
residue by chromatography on a silica gel support using dichloromethane
followed by dichloromethane/ethanol (97:3) as successive eluents gave
6-chloro-3-methoxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from n-hexane. Yield 1.21 g (m.p. 120.degree.-121.degree.
C.).
In the BICM test described above, a dosage of 100 mg/kg of this compound
inhibited 50% of the mice tested from seizures.
EXAMPLE 30
A mixture of 4,5-dihydro-1,4,-benzothiazepine-3(2H)-one (5.37 g, prepared
as example 1 of international patent application WO 92/21668) and
phosphorus pentachloride (6.3 g) in dry toluene was heated at 50.degree.
C. for two hours. The precipitated product was collected by filtration,
washed with toluene and dried to give
3-chloro-2,5-dihydro-1,4-benzothiazepine. Yield 5.2 g (m.p.
164.degree.-168.degree. C.). This crude product was used in the next step
without further purification.
3-Chloro-2,5-dihydro-1,4-benzothiazepine (5 g) and a 33% solution of
methylamine in absolute ethanol (150 ml) were heated under reflux for one
hour. The mixture was cooled and filtered. Purification of the residue by
flash chromatography using ethyl acetate/ethanol (1:1) as eluent gave
3-methylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from ethanol. Yield 0.51 g (m.p. 278.degree.-280.degree.
C.).
The ED.sub.50, in the BICM test described above, for this compound was 20.8
mg/kg.
EXAMPLE 31
Phosphorus pentachloride (5.84 g) was added in portions to a stirred
suspension of 6-chloro-4,5-dihydro-1,4-benzothiazepin-3(2H)-one (6.0 g,
prepared as example 1 of international patent application WO 92/21668) in
dry toluene (450 ml). The reaction mixture was then heated in an oil bath
at 50.degree.-60.degree. C. for 51/2 hours. After cooling, the crude
precipitate of 3,6-dichloro-2,5-dihydro-1,4-benzothiazepine was collected
by filtration, and washed with toluene. Yield 4.85 g. This crude product
was used in the next step without further purification.
A solution of aniline (4.8 ml) in dry ethanol (10 ml) was added dropwise at
room temperature to a stirred solution of
3,6-dichloro-2,5-dihydro-1,4-benzothiazepine (2.5 g) in dry ethanol (65
ml). The reaction mixture was heated under reflux for 91/2 hours, cooled
to room temperature, filtered and the solvent was removed from the
filtrate by evaporation at reduced pressure. The oily residue was
separated into fractions by chromatography on a silica gel support using
chloroform/ethanol (50:1) as eluent. Purification of those fractions
containing the product by flash chromatography using ethyl acetate/hexane
(2:3) as eluent gave
6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was
recrystallised from ethyl acetate/hexane. Yield 0.27 g (m.p.
150.degree.-152.degree. C.).
The ED.sub.50, in the BICM test described above, for this compound was 16.3
mg/kg.
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